Ca Handling and Sarcoplasmic Reticulum Ca Content in Isolated Failing and Nonfailing Human Myocardium

Disturbed sarcoplasmic reticulum (SR) Ca content may underlie the altered force-frequency and postrest contractile behavior in failing human myocardium. We used rapid cooling contractures (RCCs) to assess SR Ca content in ventricular muscle strips isolated from nonfailing and end-stage failing human hearts. With an increase in rest intervals (1 to 240 s; 37°C), nonfailing human myocardium (n57) exhibited a parallel increase in postrest twitch force (at 240 s by 121644%; P,0.05) and RCC amplitude (by 69653%; P,0.05). In contrast, in failing myocardium (n530), postrest twitch force decreased at long rest intervals and RCC amplitude declined monotonically with rest (by 2569% and 5369%, respectively; P,0.05). With an increase in stimulation frequencies (0.25 to 3 Hz), twitch force increased continuously in nonfailing human myocardium (n57) by 71617% (at 3 Hz; P,0.05) and RCC amplitude increased in parallel by 247655% (P,0.05). In contrast, in failing myocardium (n526), twitch force declined by 2967% (P,0.05) and RCC amplitude increased only slightly by 36614% (P,0.05). Paired RCCs were evoked to investigate the relative contribution of SR Ca uptake and Na/Ca exchange to cytosolic Ca removal during relaxation. SR Ca uptake (relative to the Na/Ca exchange) increased significantly in nonfailing but not in failing human myocardium as stimulation rates increased. We conclude that the negative force-frequency relation in failing human myocardium is due to an inability of SR Ca content to increase sufficiently at high frequencies and thus cannot overcome the frequency-dependent refractoriness of SR Ca release. The rest-dependent decay in twitch force in failing myocardium is due to rest-dependent decline in SR Ca content. These alterations could be secondary to depressed SR Ca-ATPase combined with enhanced cytosolic Ca extrusion via Na/Ca exchange. (Circ Res. 1999;85:38-46.)